1) Field of the Invention
The present invention relates to novel pyrrolo[2,1-c][1,4]benzodiazepine-indole derivatives, their preparation process, and uses of the same in the manufacture of medicaments. In particular, according to the present invention, the novel pyrrolo[2,1-c][1,4]benzodiazepine-indole derivatives are prepared by coupling a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) compound with an indole compound via a bridge moiety, and such derivatives are found to exhibit activities in inhibiting the growth of a variety of cancer cells.
2) Description of the Related Art
In recent years, investigators in the academic field or in Pharmacy-associated industries have made most of their efforts in researches directed to the development of antitumor or anticancer drugs.
Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of potent, naturally occurring antibiotics derived from Streptomyces species (M. D. Tendler et. al., Nature (1963), 199, 501; L. H. Hurley, J. Antibiot. (1977), 30, 349). The cytotoxic and antitumor effects of PBD compounds are believed to arise from their interaction with DNA molecules, which leads to inhibition of nucleic acid synthesis and production of excision-dependent single- and double-strand breaks in cellular DNA (K. W. Kohn, Anthramycin. In Antibiotics III Mechanism of Action of Antimicrobial and Antitumor Agents; ed. by J. W. Corcoran et. al. (Springer-Verlag, N.Y.), pp. 3-11. (1975); R. L. Petrusek, et. al. J. Biol. Chem. 1982, 257, 6207). These antibiotics have been proposed to covalently bond to N2 of guanine to form a neutral minor groove adduct (L. H. Hurley et al., Nature (1979), 282, 529; S. Cheatham et al., Med. Chem. (1988), 31, 583; J. J. Wang et al., Med. Chem. (1992), 35, 2995; J. A. Mountzouris et al., J. Med. Chem. (1994), 37, 3132).
Tomaymycin, cross-linker DSB-120 (J. A. Mountzouris et al., J. Med. Chem. (1994), 37, 3132; D. E. Thurston et al., J. Org. Chem. (1996), 61, 8141), and DC-81 (W. P. Hu et. al. J. Org. Chem. 2001, 66, 2881), the structure of which are shown below, are the best known examples of PBD analogues. 
Indole compounds are another series of compounds commonly used as medicinal compounds, e.g. as antimitotic drugs. Concerning the medical uses of indole series compounds, one can refer to, e.g. the following references: J. Med. Chem., (2001) 44:4535; J. Med. Chem., (1990) 33: 2944 and J. Med. Chem., (1986) 29:1637.
In addition, indole compounds can exert effect(s) when they are coupled with other compounds. For example, it is disclosed in F. C. Seaman et al., J. Am. Chem. Soc., (1996) 118:10052 that a diindole compound is coupled with a urea compound to serve as a bridge moiety for the inter-strand cross-linker, Bizelesin. Further, it is disclosed in Q. Zhou, et al., J. Am. Chem. Soc., (2001) 123: 4865 that an indole and a flexible alkyl chain are employed as the linker for inter-strand cross-linkers comprising (+)-cyclopropapyrroloindole [(+)-CPI] and DC-81 as their primary subunits. Referring to the following drawing, which shows the partial structure of the compound disclosed in this article, it can be seen that the DC-81 compound (a PBD analogue) is coupled to the six-membered ring moiety of the indole compound via a bridge moiety represented by the formula —(CH2)n—CO—NH—. 
While the above article provides an example of coupling DC-81 and indole, the inter-strand cross-linkers disclosed therein contain a further primary subunit (+)-CPI that renders them capable of conducting alkylation at the N3 of adenine. In addition, within the cross-linkers, it is the six-membered ring of indole that is connected to DC-81. Heretofore, no prior art reference has disclosed the formation of a useful medicinal compound by coupling a PBD compound to an indole compound using a bridge moiety via the five-membered ring of the indole compound.
Although the above-mentioned inter-strand cross-linkers were reported to have selectivity in alkylating specific nucleotide sequences and the potential in inhibiting the activities of a number of tumor cells, for pharmachemists and manufacturers in the Pharmaceutical Industry, there still exists an urgent and great need to develop novel compounds that can be easily prepared and that are suitable for use in the treatment of a variety of cancers and tumors.